Technologies for imaging and sensing using both tagged and plain nanoparticles have become of interest for use in medical imaging, and for treatment of certain disorders.
Nanoparticles may be tagged with bioactive molecules. Proteins and other molecules, such as nucleic acids, often have active sites that are capable of binding compounds of interest, or analytes, with great specificity. These analytes may be substances, such as nucleic acids or proteins, found in the bloodstream or interstitial fluid of tissues, or that may appear on cell surfaces. Nanoparticles tagged with a bioactive molecule, such as an enzyme, antibody, aptamer or other molecule, capable of selectively binding such analytes are known.
Nanoparticles, whether plain or tagged, may also be present in, or leak from, or be trapped in vasculature. In particular, they may leak from vasculature damaged by, or grown in response to presence of, tumors.
Magnetic nanoparticles, nanoparticles formed with either a core, or a layer, of a magnetic material such iron, an iron alloy, or iron oxide, can be located within a subject because of their magnetic properties.
It is known that small nanoparticles undergo a random motion induced by impact with randomly moving molecules called Brownian motion. Brownian motion can be detected and monitored with a technique called Magnetic Spectroscopy of nanoparticle Brownian Motion (MSB), described in an article published as A. M. Rauwerdink, J. B. Weaver, “Measurement of Molecular Binding Using The Brownian Motion of Magnetic Nanoparticle Probes” Applied Physics Letters 96, 033702 (2010) and on the web in Feb. 1, 2010 issue of Virtual Journal of Biological Physics Research. The method also appears on the web at http://engineering.dartmouth.edu/reu/documents/CharlieTsai_FinalReport.pdf (Tsai), and for which a copy is attached as an appendix hereto, the contents of which are incorporated herein by reference. It is also known that Brownian motion is a function of particle size, with larger, heavier, particles exhibiting smaller displacements than smaller, lighter, particles.
A basic, prior, MSB apparatus 100 is illustrated in FIG. 1. Tissue 102 that may contain magnetic nanoparticles is placed near at least one AC magnetic field driving coil 104, and may be placed between two such driving coils. In this apparatus, driving coils 104 are driven by AC field driver electronics 106, such that driving coils 104 operate as an electromagnet providing an AC magnetic field to tissue 102. One or more sensing coils 108 are provided between driving coils 104 and tissue 102, changes in the magnetic field at sensing coil 108 induce currents in coil 108, these induced currents are processed by sense amplifier and signal processing electronics 110. Nanoparticles in tissue 102 change magnetic coupling between the driving coils 104 and sensing coils 108, and Brownian motion of the nanoparticles in turn modulates that coupling, causing changes in the induced currents. Balancing coils 112 may also be provided to sense the applied AC magnetic field without influence from the nanoparticles, a signal from the balancing coils 112 may in some systems be used by electronics 110 to help isolate changes in signal from sensing coil 108 due to nanoparticles in the tissue 102. Electronics 110 produces a signal 114 representing a signal component at the sensing coils 108 due to the presence of the nanoparticles.
Since a major component of signal at the sensing coils 108 is due to the magnetic field applied by the driving coils 104, in the apparatus of Tsai the sensing coil and balancing coil are placed in series with balancing coil reversed, such that in the absence of tissue and nanoparticles 102 induced voltages in sensing and balancing coils largely cancel. In previous versions of the system it was found difficult to balance the sensing 108 and balancing coils 112 very closely so the residual is generally the limit on the sensitivity of the system.
A basic prior or traditional Magnetic Particle Imaging (MPI) system 150, as illustrated in FIG. 2, has a pair of bias-field magnets 148 oriented in opposition to each other to create a nonuniform magnetic field within the space to be occupied by tissue and nanoparticles. System 150 also has multiple sets 152, 154, 156 of driving coils and sensing coils, with each set oriented on or parallel to a different coil axis, such as Y axis 158, X axis 160, and Z axis 162. These systems are typically arranged, and magnets powered, such the vector sum of fields from each coil produce a zero field point, or “field free point” (FFP) 165 that is located within the tissue and nanoparticles to be examined. When AC driving coils are energized, the FFP will move in a cyclical manner under the influence of the driving coils, and traditional MPI signals depend on nanoparticles located where the FPP passes.
Traditional MPI systems also have DC offset magnets 170, 172, 174. Since fields in tissue are the vector sum of applied fields, and these DC offset magnets are controllable, these offset magnets effectively permits application of magnetic fields along many axes, such as axis 160, in addition to coil axes 156, 158. These magnets are controlled to scan the zone of cyclically moving FFP through tissue, thereby permitting the system to scan the tissue. MPI signals as read by the sensing coils are recorded and used to build a three dimensional map of NP distribution in the tissue.
In FIG. 2 balancing coils, driving electronics, and sensing electronics are omitted for clarity.
Traditional MPI systems rely on the FPP being literally a field-free point, where the vector sum of all applied fields, including fields from bias magnets 148, DC offset magnets 170, 172, 174, and AC driving coils, is zero. MRI imaging systems typically have a strong main magnet, with field strength ranging from about 0.2 Tesla to 3 Tesla, or even more. These main magnetic fields are strong enough that it is difficult to overcome them with DC offset magnets to produce an FPP in the tissue. For this reason, it has heretofore been thought impossible to integrate MRI and MPI for near-simultaneous dual-mode imaging.
In traditional MPI, magnetization induced by an alternating magnetic field (drive field) allowed magnetic nanoparticles (mNPs) to be imaged. Prior MPI using the FFP obtained high sensitivity by recording signal at harmonics of the AC driving field, so the signal caused by the magnetization can be isolated from the signals caused by the drive field. High sensitivity allows very low amounts of mNPs to be detected. Further, spatial selectivity was obtained from saturating the signal from mNPs at all other locations than the FFP. The FFP was scanned to produce a sequence of responses at voxels, the image being derived from signal at each voxel.
A limitation of this current MPI implementation is that high gradients are required to achieve images with reasonable resolution. Gradients of 3T/m to 9T/m are required, this requires intense fields if a volume is to be scanned that is large enough for human subjects to fit in the field.
It has not been thought possible to obtain a signal from sense coils oriented perpendicular to the alternating magnetic field because mNPs in an alternating magnetic field alone produce no magnetization perpendicular to the alternating field.
A conventional MRI machine has a large magnet (main magnet) that provides a very strong static bias field in an imaging zone, into which a subject is placed for imaging. The main magnet may be a C-shaped permanent magnet as in some smaller “open-MRI” systems, it may be a superconducting toroidal electromagnet, or may have some other configuration. Also provided in a standard MRI machine are a radio-frequency signal source with transmitter coils, antennae or emitters for applying a radio-frequency electromagnetic field to portions of the subject within the bias field, and receiver antennae or coils and electronics for measuring any response due to resonance of protons in the bias field. Additional, controllable, magnets are provided that create gradients in that field during capture of each MRI image, allowing resonance to be swept along the gradients by sweeping radio-frequency stimulus frequencies, and thereby helping to localize resonances and thereby image tissues.
Magnetic nanoparticles have been coated with proteins or other molecules capable of selectively binding to analytes. When such particles are in suspension, a change in Brownian motion as measured by MSB can be detected when the particles are exposed to the analytes.